Treating acute and chronic inflammatory diseases by blocking interleukin-1 beta (IL-12) activity is now part of clinical practice. There are 11 members of the IL-1 family and most induce inflammation. The function of one member, IL-1 family member 7 (IL-1F7), remains elusive. Since its discovery in 2000, there are only 9 papers. Of all members of the IL-1 family, IL-1F7 and IL-18 are the most closely related at the genomic level. There is one report that caspase-1 cleaves the recombinant IL-1F7 precursor and that processed IL-1F7 binds to the IL-18 receptor. However, there is no convincing data that recombinant IL-1F7 exhibits either pro- or anti- inflammatory activities. To avoid difficulties with recombinant forms, we transfected the IL-1F7 precursor into mouse and human cells and observed a profound suppression of endotoxin- and IL-12-induced pro- inflammatory cytokines. Silencing of endogenous IL-1F7 results in higher levels of pro-inflammatory cytokines. Importantly, IL-1F7 translocates to the nucleus. Thus, similar to IL-11 and IL-33, IL-1F7 appears to be a dual function cytokine, that is, functional in the nucleus as well as binding to a cell surface receptor. One hypothesis being tested is whether IL-1F7 binds to the IL-18 receptor and whether such a complex recruits the inhibitory receptor, Single Ig IL-1 Related Receptor (SIGIRR) to suppress cytokines. Another hypothesis being tested is whether the nuclear function of IL-1F7 requires Smad3, the intracellular protein that mediates TGF2 signaling. In addition to testing these hypotheses in cell cultures, we have generated a strain of mice that express human IL-1F7. IL-1F7 transgenic mice are significantly protected against the systemic and local inflammation of endotoxin, dextran sodium sulfate colitis, acute myocardial ischemic infarction and contact antigen sensitization. IL-1F7 now emerges as a major inhibitory cytokine that limits inflammation during innate immune responses. We propose to use these mice to test each of the hypotheses by creating three new strains of mice, each expressing IL-1F7 but deficient in either the IL-18 receptor, SIGIRR or Smad3. The goal of this proposal is to reveal the molecular requirements for the anti-inflammatory activity of IL-1F7. IL-1F7 appears to fill a gap in understanding how the innate immune response is regulated.